Stereoselective and stereospecific routes for the synthesis of pharmaceutically-active compounds are continually in demand. The pharmaceutical activity of a particular chemical compound often resides in one isomer. See Laird, Chem. Ind (London), 366 (1989); Powel, Ambre, and Ruo, Drug Chemistry, 245-270 (1988); Borman, Chem, Eng. News, 68, 9 (Jul. 9, 1990); and Camp, Chirality, 1, 2 (1989). An efficient synthesis of the active isomer, therefore, requires a route that is stereoselective or stereospecific.
Natural products are frequently used in the synthesis of pharmaceutically-active compounds. Hanessian, Total Synthesis of Natural Product: The "Chiron" Approach, ix (1983); Asymmetric Synthesis, Vol. 4, Chapter 1 (1984); and Coppola and Schuster, Asymmetric Synthesis (1980). Generally, natural products have a defined stereochemical configuration that can be used in the synthesis of complex compounds, or that can be used to influence the stereochemical outcome of synthetic transformations. Morrison and Mosher, Asymmetric Organic Reactions (1976).
One group of natural products that have demonstrated a utility in organic synthesis is the cinchona alkaloids. This group includes such compounds as quinine, quinidine, cinchonidine, and cinchonine. Uskokovic et al. has described a process for the conversion of cinchonine into a 1:2.4 mixture of cis and trans-hexahydroisoquinolones, respectively. Uskokovic et al., Helv. Chim. Acta, 56, 2834-2844 (1973). This mixture of cis and trans isomers was separated and reduced to prepare optically pure (4aS,8aR) and (4aS, 8aS)-octahydroisoquinolones. A stereospecific or a more stereoselective route for the synthesis of hexahydroisoquinolones would be useful for the synthesis of pharmaceutically-active compounds.
A recent report shows that a series of 6-substituted decahydroisoquinoline-3-carboxylic acids act as competitive NMDA receptor antagonists and are suitable for use as neuroprotective agents in a variety of acute and chronic neurodegenerative disorders. Ornstein et al., J. Med. Chem., 35, 3547-3560 (1992). One compound from this series, (.+-.)-(3SR,4aRS, 6SR,8aRS)-6-(phosphonomethyl)-decahydroisoquinoline-3-carboxylic acid, is a very potent and selective neuroprotective agent against excessive NMDA receptor activation in vivo in rats and in mice. Schoepp, Ornstein, Salhoff, and Leander, J. Neural Transm., 85, 131-143 (1991). This compound effectively blocks NMDA-induced convulsions in neonatal rats. This compound also provides neuroprotection against NMDA receptor-induced lethality in mature mice and rats. Surprisingly, the 3S isomer of this compound is active as an NMDA receptor antagonist, while the 3R isomer is inactive. Ornstein & Klimkowski, Excitatory Amino Acid Receptors: Design of Agonists and Antagonists, 183-200 (1992). This agent, as well as other compounds in the series, may prove therapeutically useful in treating acute pathological conditions that involve glutamate excitotoxicity. Therefore, an efficient stereocontrolled synthesis of these compounds is desired.